Labdane Research Articles

P-282 - Mitochondrial dysfunction of halimane and labdane diterpenes in human lung cancer cells

Mitochondrial dysfunctions have been associated with several malfunctions such as increase of ROS and uncontrolled M. tuberculosis (Mtb) replication (1,2). The electrochemical gradient produced by mitochondria generates the mitochondrial membrane potential (MMP), which is a key parameter for evaluating mitochondrial function (2). Since the coexistence of tuberculosis and lung cancer has remained controversial, one halimane (HAL: (11 R*,13E)-11-acetoxyhalima-5,13-dien-15-oic acid) and two labdane diterpenes PLEC: Plectrornatine C and the MRC: 1:1 mixture of 1,6-di-O-acetylforskolin:1,6-di-O-acetyl-9-deoxyforskolin), previously isolated from Plectranthus spp.,(3) were evaluated for the mechanisms of cell death associated with mitochondrial dysfunction. The ROS level and evaluation of the MMP revealed that only HAL decreased mitochondrial membrane potential. In conclusion, the halimane diterpene (HAL) seems to particularly have a cytotoxic effect associated with mitochondrial dysfunction on lung cancer cells that may be further evaluated on the uncontrolled Mtb replication mechanism.

Human serum albumin binding to the biologically active labdane diterpene “leoheterin”: Spectroscopic and in silico analysis

Labdane diterpenes are important substances due to their remarkable biological activities such as, antibacterial, antiprotozoal, antifungal and cytostatic and cytotoxic effects against human cancer cells. We have isolated a labdane diterpene named “leoheterin” from the aerial parts of the Otostegia fruticosa Forssk (Briq) obtained from south west Arabian mountains of Saudi Arabia. The isolated compound was characterized by 1HNMR, 13CNMR, IR and UV–visible spectroscopies. Due to the pharmaceutical importance of this class of compounds we have studied the interaction of HSA with leoheterin by using several spectroscopic methods. The change in the UV spectrum of HSA in presence of leoheterin gives a primary idea about the interaction between them. Congruently, leoheterin quenches the fluorescence of HSA with a prominent blue shift of 5 nm, reminiscent of involvement of hydrophobic interactions. There was 1:1 binding between leoheterin and albumin which was taken place via static quenching mechanism. From CD it was revealed that leoheterin induces the secondary structure of HSA which is further supported by 3-d fluorescence measurements which shows a decrease in the size of the HSA-leoheterin complex as compared to the HSA alone. Molecular docking simulations presented that among the first three conformers, which have been arranged according to the least binding energies and are also in good corroboration with the free energies of binding obtained experimentally, the first two conformers shown the binding in hemin binding site of subdomain IB while in third conformer the binding site was near to the drug binding site 1 located in subdomain IIA. All conformers exhibited the involvement of hydrogen bonding as well as hydrophobic interactions.

Camphor sulphonic acid mediated quantitative 1,3–diol protection of major Labdane diterpenes isolated from Andrographis paniculata

Phytochemical survey of the methanol extract of the dried aerial parts of Andrographis paniculata led to the isolation of major labdane diterpenes, namely 14-deoxy-11,12-didehydroandrographolide, andrographolide and neoandrographolide. Andrographolide was found to be the major phytoconstituent of the plant which was biologically active. For better physiochemical characteristics and bioefficacy, andrographolide is subjected to semi-synthetic modifications. However, presence of several free hydroxyl groups associated with this molecule make it quite polar and poorly soluble in many organic solvents and hence unsuitable for synthetic modifications. One way of resolving its solubility issue is to protect 1,3-diol quantitatively under mild reaction condition without effecting other functional groups. Reaction conditions were optimised using different solvent systems and catalysts towards this direction. X-ray structure of 3,19-isopropylidene-14-deoxy-11,12-didehydroandrographolide is being reported here for the first time. Isolated compounds and derivatives were confirmed by spectral analysis or X-ray data analysis.

Chemical constituents from Elytropappus rhinocerotis (L.f.) Less.

Phytochemical investigation of the ethyl acetate extract of the aerial parts of Elytropappus rhinocerotis (L.f.) Less. led to the isolation of a coumarin (1), four flavonoids (2–5), and four labdane diterpenes (6–9). The structural characterization of the isolated compounds was based on spectroscopic data. All compounds are reported for the first time from this species and from the genus Elytropappus Cass. The isolation of labdane diterpenes and methoxylated flavones is of taxonomical significance.

New tetranorlabdane diterpenoids from the fruits of Elettaria cardamomum Maton

A pair of new tetranorlabdane diterpenoid epimers, named elettarins A (1) and B (2), together with five known labdane diterpenes (3–7), were isolated from Elettaria cardamomum Maton. The structures of elettarins A and B were established based on spectroscopic data (HRESIMS, 1D/2D NMR), and ECD experimentation. All isolates were evaluated for their inhibitory activities against nitric oxide (NO) production on BV-2 microglia cells.

Cytotoxic labdane diterpenes and bisflavonoid atropisomers from leaves of Araucaria bidwillii

Chemical investigation of a methanolic extract of leaves from Araucaria bidwillii (Araucariaceae) from Egypt afforded four new labdane diterpenoidal metabolites (1–4) together with one known diterpene, 7-oxocallitrisic acid (5), two triterpenoidal metabolites, 2-O-acetyl-11-keto-boswellic acid (6) and β-sitosterol-3-O-glucopyranoside (7), phloretic acid (8), and two methylated bisflavonoids, agathisflavone-4′,7,7″-trimethyl ether (9) and cupressuflavone-4′,7,7″-trimethyl ether (10). The new metabolites 1–4 were unambiguously identified by applying extensive 1D and 2D NMR spectroscopic studies as well as HRESIMS. The relative and absolute configurations of 1–4 were determined using ROESY and the modified Mosher's method, respectively. All isolated compounds were assessed for their antimicrobial, antitubercular and cytotoxic activities. Among the tested compounds, the new labdane diterpenes 1–4 revealed significant cytotoxic activity against mouse lymphoma L5178Y cell line with IC50 values ranging from 1.4 to 12.9 μM, respectively.

Total Synthesis of the Labdane Diterpenes Galanal A and B from Geraniol.

The first total synthesis of galanal A and B has been achieved from naturally occurring geraniol. Key steps in this synthesis are the use of a Lewis acid assisted chiral Brønsted acid (chiral LBA) mediated cationic polyene cyclization and a titanocene-mediated radical cyclization for the asymmetric assembly of the "AB" ring and the construction of the all-carbon quaternary center at the junction of the "BC" ring, respectively.

Semisynthetic Esters of 17-Hydroxycativic Acid with in Vitro Cytotoxic Activity against Leukemia Cell Lines.

A collection of sixteen semisynthetic 17-hydroxycativic acid esters with alcohols containing a tertiary amine group was evaluated for their in vitro cytotoxicity against two human cancer cell lines, THP-1 and U937, and for their effects on the cell cycle and cell death. While 17-hydroxycativic acid itself is not cytotoxic, all the esters displayed cytotoxic activity, with 50% growth inhibition (GI50) values ranging between 3.2 and 23.1 µM. In general, the most potent compounds in both cell lines were esters with four carbon long alcohol residues. There was no clear relationship between the identity of the terminal secondary amine and the activity of the compound. Experiments using the 6-(pyrrolidin-1-yl)pentyl ester, 2c, revealed that this compound activates caspases-3/7 and causes poly(ADP-ribose)polymerase 1 (PARP-1) fragmentation in THP-1 and U937 cells, indicating the induction of apoptotic cell death. These results suggest that further investigation into the anticancer activity of diterpene derivatives and other labdane diterpenes may be fruitful.

Three new labdane diterpenes from Loxocalyx urticifolius

Three new labdane diterpenes, namely loxocalyxin D (1), loxocalyxin E (2) and 13-epiloxocalyxin E (3), were isolated from the whole plants of Loxocalyx urticifolius Hemsl. Their structures were elucidated by extensive spectral analysis and chemical methods. The absolute configuration of loxocalyxin D (1) was confirmed by X-ray crystallographic analysis. The cytotoxic activities of the isolated labdane diterpenes were evaluated against the four human cancer cell lines A549, HepG2, HL-60 and MCF-7. 13-epiloxocalyxin E (3) exhibited selective cytotoxicity against A549 and MCF-7 with the IC50 values of 22.4 and 47.3μM, respectively.

Antileishmanial Activity of Labdane Diterpenes Isolated from Alpinia nigra Seeds

Antileishmanial Activity of Labdane Diterpenes Isolated from Alpinia nigra Seeds

Biological Evaluation of Terrestrial and Marine Plant Originated Labdane Diterpenes (A Review)

Recent progress on studies of labdane diterpenoids is compiled. Seventy seven biologically active labdane diterpenes isolated from various higher plants, mosses, liverworts, algae, etc. are reported. The absolute configurations of compounds 1 – 77 were established using extensive spectroscopic techniques. The wide range of biological activities possessed by these diterpenoids suggests that thorough evaluation of some structure-activity relationships is overdue. In this review, data on the natural sources, isolation, structure and biological activities of labdane diterpenoids isolated from various plants are summarized.

Antileishmanial Activity of Labdane Diterpenes Isolated from Alpinia nigra Seeds

Antileishmanial Activity of Labdane Diterpenes Isolated from Alpinia nigra Seeds

Labdane Diterpenes from the Fruits of Sinopodophyllum emodi.

Two new labdane diterpenes, sinoditerpene A (1) and B (2), were isolated from the fruits of Sinopodophyllum emodi, along with two known analogues 3 and 4. Their structures were established on the basis of extensive spectroscopic analysis. The isolation of compounds 1–4 represents the first report of diterpenes from the genus Sinopodophyllum. The cytotoxic activities of all isolated compounds were evaluated in comparison with 5-fluorouracil against the MCF-7 and HepG2 cell lines, towards which 3 showed more potent cytotoxicity.

New Labdane diterpenes from Hedychium yunnanense with cytotoxicity and inhibitory effects on nitric oxide production

Two new labdane diterpenes, hedychenoids A (1) and B (2), were isolated from the rhizomes of Hedychium yunnanense, together with four known ones hedychenone (3), forrestin A (4), villosin (5) and calcaratarin C (6). Their structures were determined on the basis of NMR (1D and 2D) and mass spectroscopic analysis. Compounds 2, 3 and 5 exhibited cytotoxicity against SGC-7901 with IC50 values of 14.88 ± 0.52, 7.08 ± 0.21 and 7.76 ± 0.21 μg/ml, 3 and 5 against HeLa with IC50 values of 9.76 ± 0.48 and 13.24 ± 0.63 μg/ml, respectively. Compounds 2, 5 showed inhibitory effects against nitric oxide production in LPS and IFN-γ-induced RAW 264.7 murine macrophages with IC50 values of 6.57 ± 0.88 and 5.99 ± 1.20 μg/ml, respectively.

ChemInform Abstract: New Labdane Diterpenes and Their Glycoside Derivatives from the Roots of Isodon adenantha.

Abstractisolation, structure, cytotoxicity and antibacterial activities of two new labdane diterpenes, adenanthic acids A (I) and B (II), three new labdane diterpene glycosides, adenanthosides A‐C (II), together with 23 known constituents

Antitubercular Activity Increase in Labdane Diterpenes from Copaifera Oleoresin through Structural Modification

The labdane diterpenes copalic acid, 3β-acetoxy-copalic acid, 3β-hydroxy-copalic acid and ent-agathic acid were isolated from Copaifera langsdorffii oleoresin. These four compounds were submitted to structural modifications by reduction with hydrogen/palladium, esterification with diazomethane, esterification with methanol/sulfuric acid and conversion into sodium salt, furnishing 15 compounds. All compounds were assayed in vitro against Mycobacterium tuberculosis (H37Rv, ATCC 27294). The four compounds displayed minimum inhibitory concentration (MIC) value of 125 μg mL, and were not considered active. A methylated derivative of compound 3β-hydroxy-copalic acid, and a sodium salt of copalic acid displayed MIC values of 25 μg mL (71.7 μM) and 6.25 μg mL (19.2 μM), respectively. The sodium salt of copalic acid stood out by displaying similar activity in comparison with streptomycin (MIC 6.25 μg mL) and a better activity compared to μM value of pyrazinamide (MIC 3.12 μg mL; 25.34 μM). Therefore, the methylated derivative of compound 3β-hydroxy-copalic acid and the sodium salt of copalic acid should be considered for further studies.

The effects of supplemented diets with a phytopharmaceutical preparation from herbal and macroalgal origin on disease resistance in rainbow trout against Piscirickettsia salmonis

The present study aimed to evaluate the effects of a commercial phytopharmaceutical preparation from herbal and macroalgal origin on the growth and immune response of rainbow trout adapted to seawater and its susceptibility to Piscirickettsia salmonis infection. Preliminary in vitro trials, evaluated the effects of the commercial product Futerpenol® on the expression levels of selected immune-regulatory genes and its protective effect in a challenge against Piscirickettsia salmonis (LF89). Subsequent in vivo feeding trials were conducted to corroborate fish protection against Piscirickettsia salmonis. Control and treatment diets (with or without the commercial product Futerpenol® at a concentration of 1kg/ton) were fed to triplicate groups of 50 fish (average weight: 100.1±11.1g) during 30days. Fish from all dietary groups were equally redistributed in three tanks and challenged by cohabitation with fish infected with P. salmonis (shedders) at the end of the feeding treatment, and mortalities were recorded over 80days post-infection. A cumulative mortality of 35.0±4.3 and 15.0±6.0% was registered when challenged fish were previously fed during 30days with the control and treatment diets respectively. Futerpenol® dietary administration preceding the cohabitation challenge gave significant protection from P. salmonis as suggested by the Relative Percent Survival (RPS) values of 62.3 and 57.1% after 60 and 80days post-infection, respectively. These results suggest that dietary supplementation with Futerpenol® at 1kg/ton do not affect growth performance and strengthen immunity of Oncorhynchus mykiss against P. salmonis under the experimental conditions applied during this study. Statement of relevanceThis study demonstrates that dietary supplementation with a phytopharmaceutical preparation, rich in fucoidans and labdane diterpenes strengthen immunity of O. mykiss against P. salmonis. The use of feed supplemented with this kind of phytopharmaceutical preparations in anticipation to potential infections or vulnerable stages of the production could be useful as an alternative method to prevent and limit the outbreak of salmonid rickettsial septicaemia (SRS) which constitutes one of the main infectious diseases causing production problems and substantial loss in salmonids and marine fish aquaculture worldwide.

Inhibition of human neutrophil elastase by labdane diterpenes from the fruiting bodies of Ramaria formosa.

Two new labdane diterpenes (1 and 2) were isolated from the fruiting bodies of Ramaria formosa. The structures of these compounds were established by extensive spectroscopic studies and chemical evidence. The inhibitory activity of compounds 1 and 2 against human neutrophil elastase (HNE) was evaluated in vitro. Compounds 1 and 2 inhibited HNE activity moderately. The IC50 values for compounds 1 and 2 were 36.4 ± 1.2 and 40.8 ± 1.5 μM, respectively; the IC50 value for the positive control, EGCG, was 12.5 ± 0.8 μM. In addition, the mechanism by which 2 inhibited HNE was a mixed-type noncompetitive inhibition, with a Ki of 41.5 ± 1.8 μM.

Combined metabolome and transcriptome profiling provides new insights into diterpene biosynthesis in S. pomifera glandular trichomes.

BackgroundSalvia diterpenes have been found to have health promoting properties. Among them, carnosic acid and carnosol, tanshinones and sclareol are well known for their cardiovascular, antitumor, antiinflammatory and antioxidant activities. However, many of these compounds are not available at a constant supply and developing biotechnological methods for their production could provide a sustainable alternative. The transcriptome of S.pomifera glandular trichomes was analysed aiming to identify genes that could be used in the engineering of synthetic microbial systems.ResultsIn the present study, a thorough metabolite analysis of S. pomifera leaves led to the isolation and structure elucidation of carnosic acid-family metabolites including one new natural product. These labdane diterpenes seem to be synthesized through miltiradiene and ferruginol. Transcriptomic analysis of the glandular trichomes from the S. pomifera leaves revealed two genes likely involved in miltiradiene synthesis. Their products were identified and the corresponding enzymes were characterized as copalyl diphosphate synthase (SpCDS) and miltiradiene synthase (SpMilS). In addition, several CYP-encoding transcripts were identified providing a valuable resource for the identification of the biosynthetic mechanism responsible for the production of carnosic acid-family metabolites in S. pomifera.ConclusionsOur work has uncovered the key enzymes involved in miltiradiene biosynthesis in S. pomifera leaf glandular trichomes. The transcriptomic dataset obtained provides a valuable tool for the identification of the CYPs involved in the synthesis of carnosic acid-family metabolites.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2147-3) contains supplementary material, which is available to authorized users.

Diterpenes and kawalactone from the rhizomes of Amomum uliginosum J.Koenig

Seven compounds, including three labdane diterpenes (1, 4, 6), one bisnorlabdane diterpene (2), one steroid (3), one sesquiterpene (5) and one kawalactone (7) were isolated from the rhizomes of Amomum uliginosum J.Koenig. Compounds 1–4, 6 and 7 were firstly isolated from the genus Amomum. This work represented the first phytochemical study on this plant. The chemotaxonomic significance of these compounds was summarized.